Why patients with type 1 diabetes are faced with the highest mortality from cardiovascular disease (CVD) compared to the general population, and can benefit from intensive diabetes therapy for both glycemic & nonglycemic CVD risk.

Though the mechanism isn’t clear and with little evidence on how to properly treat or prevent mortality due to CVD, there are ongoing studies to determine the role of glycemic control in patients with type 1. Previous studies have recognized hyperglycemia more clearly as a risk factor for clinical cardiovascular outcomes in patients with type 1. Glycemic levels that are poorly controlled result in traditional CVD risk factors, classified as “systolic and diastolic blood pressure, pulse pressure and pulse rate, triglycerides, LDL cholesterol, and HDL cholesterol”.

The Diabetes Control and Complication Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study performed a randomized controlled trial and observational study with the goal to identify risk factors in the causal pathway linking hyperglycemia and the risk of CVD. The authors wanted to determine “the extent to which the effect of glycemia (HbA1c) on the risk of CVD is potentially mediated by their traditional CVD risk factors”.

The study participants with type 1 were randomized into two groups, one group (n = 711) receiving intensive diabetes therapy (IDT) and the other group (n = 730) conventional therapy (CON). The IDT group goal was to obtain close to nondiabetic glycemic levels (HbA1c) if able to be done safely, whereas the CON group had no prespecified glucose targets, the researchers wanted to only maintain their clinical well-being. Both groups underwent testing to determine their cardiovascular risk factors, such as physical examination, collection of blood and urine samples, HbA1c, and fasting lipids (LDL calculated via the Friedewald equation). HbA1c was measured quarterly during DCCT and annually during EDIC, and fasting lipids were measured annually during DCCT and every other year during EDIC. Researchers were to then document any CVD events experienced, as well as any major atherosclerotic cardiovascular events (MACE).

To assess the effect of covariates on the risk of developing CVD event, Cox proportional hazards models were used. All models were adjusted for age at baseline due to age being the strongest risk factor of CVD events.

HbA1c was determined the second strongest risk factor for CVD after age. An increase in HbA1c by 1 unit increased the risk of any-CVD by 50% (P < 0.0001). Likewise, a 68% increased risk of MACE was determined (P < 0.0001). The researchers then adjusted what they considered as potential mediating risk factors one by one for both any-CVD as well as MACE. With adjustment, data still resulted as a highly significant association (P < 0.0001). The researchers then examined the effect of the two treatments groups on the risk of any-CVD and MACE. The data indicated that the mean updated HbA1c completely mediated the effect of treatment group. Aggressive glycemic management long-term plays a role in CVD risk reduction but isn’t enough alone.

Knowing the effects of long-term hyperglycemia and its role on CVD risk is important in efforts to reduce CVD morbidity and mortality in patients with type 1. The researchers’ findings determine that the risk of any-CVD and MACE are strongly associated with the mean HbA1c. While it is important to control the HbA1c, it is also important to control the levels of the non glycemic risk factors, as it can help with a ~50% reduction on the effect of glycemia on the risk of CVD. The authors suggest that patients with type 1 should receive both aggressive management of their glycemic levels and the levels of the non glycemic CVD risk factors to receive the best outcome.

Practice Pearls:

Patients with type 1 have a higher rate of mortality due to cardiovascular disease.

The study determined that not only controlling glycemic levels is important, but controlling mediating risk factors for CVD can also decrease the effect of glycemia on the risk of CVD.

]]>Blood Pressure or Glucose: Which to Treat More Aggressively?http://www.diabetesincontrol.com/blood-pressure-or-glucose-which-to-treat-more-aggressively/
Tue, 07 May 2019 00:09:12 +0000http://www.diabetesincontrol.com/?p=69074

About 25% of people with type 1 diabetes and 80% of people with type 2 diabetes have high blood pressure. Having diabetes raises your risk of heart disease, stroke, kidney disease and other health problems. Having high blood pressure also raises this risk.

A study published in the journalHypertension, where researchers conducted a post hoc analysis of the ADVANCE trial involving nearly 11,000 patients with diabetes and at a moderate to high risk for atherosclerotic cardiovascular disease, ages younger than 80, found that those who received perindopril-indapamide therapy for blood pressure control experienced reductions in all-cause mortality and major vascular events over 4.3 years, regardless of whether baseline systolic BP was above or below 140 mm Hg, compared with those on placebo.

The researchers compared outcomes between moderate- to high-cardiovascular risk people with type 2 diabetes and hypertension—a condition defined as persistently elevated blood pressure—receiving anti-hypertension combination treatment (perindopril and indapamide) and people with diabetes and hypertension receiving placebo. This trial had already reported benefit overall for the additional hypertension treatment; however, it was not known whether this benefit also applied to people with diabetes who started off with a blood pressure below 140/90 mm Hg. To determine treatment benefit, the analysis compared rates of overall death from any cause as well as the rate of major vascular events, including heart attacks, strokes, diabetes-related kidney disease, and diabetes-related eye damage.

Both patients at higher baseline risk for cardiovascular disease and those with lower cardiovascular risk benefitted from the more intensive treatment. In addition, those with diabetes and with blood pressures in the 130/80 mm Hg to 140/90 mm Hg range before starting the trial benefited from more intensive therapy, achieving lower blood pressures during the trial.

During the study, there were 837 deaths and 966 major vascular events, a category that includes heart attacks, strokes, diabetic kidney disease, and diabetic eye disease. The group receiving intensive blood pressure therapy experienced 9% fewer events and 14% fewer deaths than the group taking placebo.

Untreated hypertension fuels the risk for cardiovascular issues, including heart attacks and strokes, while diabetes drives cardiovascular risk independently of high blood pressure. The simultaneous occurrence of hypertension and diabetes dramatically magnifies a person’s risk for cardiovascular disease.

In the post hoc analysis, those effects held whether baseline 10-year atherosclerotic cardiovascular disease (ASCVD) risk was more or less than 20% and whether baseline systolic BP was above or below 140 mm Hg,

The study makes the case for more intense BP treatment among individuals with diabetes mellitus, in line with the SPRINT study of only patients without diabetes, the authors said. The findings also support the 130/80 mm Hg BP target now endorsed by national guidelines.

SPRINT showed in 2015 that lowering systolic BP to a target under 120 mm Hg among high-risk individuals without diabetes was associated with reduced risk of heart attack, stroke, or death. In diabetes, though, going as low as 120 mm Hg did not translate into a reduction in the primary combined cardiovascular outcome of the ACCORD trial.

However, ACCORD does not rule out benefit to a target <130 mm Hg and, indeed, showed a trend toward benefit of intensive BP control to <120 mm Hg with a significant reduction in stroke and a point estimate for the primary composite outcome that was in favor of intensive therapy.

ADVANCE, like ACCORD, was a trial with 2×2 factorial design investigating intensive glucose and BP lowering separately in diabetes. Both trials showed tight glucose control was a flop. But in ADVANCE, BP control with perindopril-indapamide therapy was associated with benefits even when patients started out under 140 mm Hg in systolic BP.

Patients randomized to the perindopril-indapamide group experienced more cough, hypotension, and dizziness compared to placebo, but such adverse events led to permanent discontinuation at similar rates across BP and ASCVD risk subgroups.

Practice Pearls

People with type 2 diabetes who received intensive treatment to keep their blood pressure levels at 130/80 mm Hg or below had fewer heart attacks, strokes, and other diabetes complications.

Results suggest that blood pressure levels of 130/80 mm Hg or lower can benefit patients at various degrees of baseline blood pressure elevation and with different cardiovascular risk—a composite score that estimates a person’s likelihood of having a heart attack or stroke within 10 years.

Increased cardiovascular risk found in women with glucose concentrations at the upper end of the normal range during pregnancy.

Glucose screening during pregnancy can predict future cardiovascular (CV) risk in women with and without gestational diabetes, according to study results published in The Lancet Diabetes & Endocrinology. CV risk was found to be higher with abnormal glucose screening tests, but there was also increased CV risk in women with glucose concentrations at the upper end of the normal range.

In studies to date, gestational diabetes has consistently been associated with an increased future risk of cardiovascular disease, irrespective of the antepartum screening protocol or diagnostic criteria by which gestational diabetes is diagnosed. Previous studies have shown gestational diabetes is a risk factor for CV morbidity. The study investigators hypothesized that glucose screening during pregnancy can predict CV disease in women who do not have gestational diabetes. The goal of their study was to investigate the association between glucose challenge test results during pregnancy and future CV risk in the general obstetrical population and women without gestational diabetes.

The investigators reasoned that the resultant heterogeneity in the severity of dysglycemia in women with gestational diabetes suggests that the relationship between gestational glycemia and subsequent cardiovascular disease probably extends into the non-diagnostic range. So, they hypothesized that glucose screening in pregnancy would identify future risk of cardiovascular disease in women who did not have gestational diabetes.

The retrospective population-based cohort study used administrative databases from the Ministry of Health and Long-Term Care of Ontario, Canada. The study enrolled all women in the Ontario database who had a 50-g oral glucose challenge test during pregnancy at between 24 and 28 weeks’ gestation and who delivered between July 2007 and December 2015.

Gestational diabetes was defined as 1-hour post-challenge plasma glucose concentration ≥200mg/dl(11.1 mmol/L) or a result between 140mg/dL.and 195mg/dL.(7.8 and 11.0 mmol/L) with a record of a diabetes diagnosis on the delivery hospital record. The participants were divided into 6 equal groups based on the glucose screening test results to: ≤86mg/dL to 89mg/dL.(4.8 – 4.9 mmol/L;) to 100mg/dL.(5.5 mmol/L) 100-115mg/dL.(5.6 to 6.2 mmol/L); 115-125mg/dL.(6.3 to 6.9 mmol/L) 126-143mg/dL.(7.0 to 7.9 mmol/L); and ≥145mg/dL(8.0 mmol/L.)

259,164 women were identified as eligible for this study: 13,609 who had gestational diabetes, and 245,555 women without gestational diabetes. The women were followed up over a median 3·9 years (IQR 2·8–5·6) for the development of cardiovascular disease. Each 1 mmol/L increment in the glucose challenge test result was associated with a 13% higher risk of cardiovascular disease (after adjustment for age, ethnicity, income, and rurality, adjusted hazard ratio [HR] 1·13, 95% CI 1·04–1·22). This relationship persisted after excluding women with gestational diabetes (1·14, 1·01–1·28). In women without gestational diabetes, those with an abnormal glucose challenge test result (140mg/dL.)(≥7·8 mmol/L) and those with a result between 130mg./dL. and 140mg/dL.(( 7·2 and 7·7 mmol/L) had an increased risk of cardiovascular disease (HR 1·94, 95% CI 1·29–2·92; and 1·65, 0·99–2·76, respectively), compared with those with a result of 128mg/dL.(7·1 mmol/L) or less (overall p=0·003).

In the group of women without gestational diabetes, CV risk was higher in patients with an abnormal glucose screening test 140mg/dL. (≥7.8 mmol/L), but there was also increased CV risk in patients with a glucose concentration at the upper end of the normal range

“Glucose screening of pregnant women that is done in current obstetrical practices offers the capacity to identify future risk [for CV disease] in both those with gestational diabetes and those who are classified clinically as not having gestational diabetes,” concluded the researchers.

Practice Pearls

Glucose screening during pregnancy can help identify future cardiovascular risk among women with and without gestational diabetes.

Each 1 mmol/L increment in the glucose challenge test result was associated with a 13% higher risk of cardiovascular disease

The relationship between gestational glycaemia and subsequent risk of cardiovascular disease extends into the normoglycemic range.

Recently a pump user reported a sudden increase in her glucose levels lasting a couple of days. Her blood sugars were elevated to 275-320mg/dL, with no ketones present. Changing her infusion sets did not help. Nor did rotating to a new injection site or even using a fresh vial of insulin. After reviewing her insulin pump we noticed a symbol on her “home screen” saying that a special feature was running.

Recently a pump user reported a sudden increase in her glucose levels lasting a couple of days. Her blood sugars were elevated to 275-320mg/dL, with no ketones present. Changing her infusion sets did not help. Nor did rotating to a new injection site or even using a fresh vial of insulin. After reviewing her insulin pump we noticed a symbol on her “home screen” saying that a special feature was running. Upon investigating, we found that she accidentally switched the pump to the secondary basal pattern with the rate set at 0.0 units/hr. Reverting back to the standard basal program and deactivating the extra basal programs led to the resolution, and blood sugars were normalized.

Bottom Line:

As a pump trainers we should know that many times when it comes to how to change pump settings, most patients don’t have a clue, as it may not have been explained properly to them when they were educated. This happens because they may go for a very long time on the first settings in their pump and never get a chance to practice. Setting a second basal program happens quite often as the patient sees their clinician and is instructed to change rates but is not sure how to do it and accidently sets up a second bolus. Experience shows that many users feel if they go back to the home screen they can undo whatever they have done. As a way to protect your patients from this, ask them to call the support center of their respective company and let them walk the patient through the changes.

David L. Joffe, BSPharm, CDE, FACAEditor in Chief, Diabetes in Control

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All individuals with type 1 diabetes and many patients with type 2 diabetes are required to take insulin to manage their blood glucose levels. The main routes of administration most commonly consist of an insulin pump or injection with a needle or pen. Insulin pumps are small computerized devices designed to administer insulin via a thin flexible tube that is inserted subcutaneously. These devices usually deliver insulin either as a continuous steady dose or as a bolus dose, per patient’s demand. Insulin pumps have been used amongst all ages successfully; however, their use has been more popular within young patients with type 1 diabetes.

A previous study assessed the In-home use of the MiniMed 670G hybrid closed-loop system for 3 months by adolescents and adults with type 1 diabetes. The results of this trial indicated that using the MiniMed 670G hybrid closed-loop system leads to an improvement in HbA1c. Additionally, another study evaluated the glycemic outcomes of in-home use of the same system by children. This study compared the data to those of the adolescent and adult from the previous study and suggested that using the MiniMed 670G system improved glycemic outcomes of children with type 1 diabetes, comparable to what was observed for adolescents and adults(P<0.001).

A new observation study has been conducted from 5/30/17 to 9/7/18 at Boston Children’s Hospital on 93 patients (age range 6–25 years) with type 1 diabetes mellitus who chose to be on a Medtronic 670G hybrid closed-loop insulin pump to manage their diabetes. All participants were trained and started on the Medtronic 670G in auto mode. In 2016, the Medtronic MiniMed 670G hybrid closed-loop insulin pump was FDA approved as the first artificial pancreas system for patients with a minimum age of 14 years. In 2018, a broader indication got approved for the system, which includes patients with a minimum age of 7 years.The insulin pump was matched with the Guardian 3 sensor. Although the Medtronic MiniMed 670G hybrid closed-loop insulin pump is FDA cleared to be placed on upper arms and abdomen, the majority of participants placed the device on their stomach area.

This observation trial revealed that 38% (n=35) of participants in the study who used a hybrid closed-loop insulin delivery system discontinued the use of this device within a few months. However, 62% (n=58) of the study participants continued to use the system during the follow-up period (mean follow-up of 8 months). A significant drop from the baseline in HbA1c was noted after six months, among the patients who continued using the Medtronic MiniMed 670G hybrid closed-loop insulin pump. However, it appeared that past the 6-month period, there was a negative effect on HbA1c and causing the HbA1c level to increase. The rise in HbA1c levels caused the HbA1c to no longer be significantly lower than baseline. The HbA1c levels measured during this study are as follows:

Average baseline HbA1c: 7.97

Average drop in HbA1c within 6 months: 0.27 (P=0.02)

Average drop in HbA1C from 6-12 months: 0.18 (P=0.16)

Average drop in HbA1C from 12-24 months: 0.03 (P=0.88)

Researchers suggest that the problem staying in auto mode, when using the Medtronic MiniMed 670G hybrid closed-loop insulin pump, seems to be the main issue, leading to the high discontinuation rate. Additionally, frequent alarms, untimely sensor failure, recurrent requirement of calibration, skin adhesion difficulties, and sensor supply issues were other problems that caused participants to stop using the system.

Results showed that the percentage of time spent in auto mode ranged from as little as 10%, up to 90% of the time, within the group of individuals who continued to use the system through the average 8-month follow-up time. Furthermore, an association between the percentage of time spent in auto mode and average HbA1c levels was noted from the data analysis. Participants who spent 57%-74% of time in auto mode and those who have more than 74% of time in auto mode had the most improved HbA1c levels (HbA1c: 7.5-8). Individuals who spent less than 35% of the time in auto mode had an average HbA1c of 8.4%.

This study concluded that the closed-loop insulin delivery in patients with type 1 diabetes who can use the system efficiently causes reduction in HbA1C levels and improves glucose management. Additionally, researchers recommend that because technical difficulties associated with the closed-loop insulin pump systems seem to be the biggest burden for patients, less frequent alarms and fewer exits from auto mode may cause an improvement in the user interface, which eventually leads to more patients continuing to use the system.

Newer updates to improve the MiniMed 670G system have been done since the study, which includes a software update that helps to remove the safety check for a continuous blood glucose entry request in some instances, and a new transmitter that transmits the information from the sensor to the pump.

Practice Pearls:

Using the MiniMed 670G system can effectively help manage diabetes for children, adolescents and adults with type 1 diabetes.

Approximately 40% of patients who have type 1 and used the closed-loop insulin delivery system quit the system within a few months.

Technical difficulties associated with the closed-loop insulin pump systems seem to be the biggest burden for patients.